The p53 tumor suppressor gene is well suited for analysis of mutational spectrum in human cancers because: a) it's the most common genetic lesion in human cancers, b) of its reasonable size as a molecular target, and c) it may indicate selection of mutations with pathobiological significance. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain and lymphoid malignancies. Mutational hotspots at CpG dinucleotides in codons 175, 245, 248, 273 and 282 may reflect endogenous mutagenic mechanisms, e.g., deamination of 5-methylcytosine to thymidine. Oxy-radicals including nitric oxide may enhance the rate of deamination. G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung, breast, esophagus and liver, and are most likely to be due to bulky carcinogen-DNA adducts. G to T transversion is more common in lung cancers from smokers when compared to never smokers. The high frequency of p53 mutations in the nontranscribed DNA strand is a reflection of strand specific repair. p53 mutation also generally indicates a poor prognosis. In geographic areas where hepatitis B virus (HBV) and aflatoxin B1 are cancer risk factors, most mutations are at the third nucleotide pair of codon 249. In geographic areas where hepatitis B and C viruses-but not aflatoxin B1-are risk factors, the p53 mutations are distributed in numerous codons. HBV X protein complexes with the p53 protein and inhibits its sequence specific DNA binding and transactivating capacity. The transactivating function of p53 also may be modulated by its redox state. The induction of skin carcinoma by ultraviolet light is indicated by the occurrence of p53 mutations at dipyrimidine sites including CC to TT double base changes. In summary, these differences in mutational spectrum among human cancer types suggest the etiological contributions in both exogenous and endogenous factors to human carcinogenesis and hypotheses for further investigation.